DESCRIPTION: The aims of this proposal are directed toward the understanding of the structure and function of the CIC family of voltage-gated chloride channels. Mutations within the gene encoding the CIC-1 channel in human or goat skeletal muscle have been shown by a number of groups, including the applicant's, to result in inherited forms of myotonia congenita. The applicant has also contributed to the analysis of how these mutations affect channel function by characterizing wild-type and mutant channels in transfected HEK293 cells using electrophysiological methods. These naturally occurring mutations have provided a framework on which to generate further mutations by site-directed methods with the aim of mapping channel domains that constitute the voltage sensor and ion pore. In addition, the applicant proposes to delineate the transmembrane topology of the CIC channel using a glycosylation tagging method that has previously been employed to generate a topological model of AMPA-type glutamate receptors.